Background & Aims-The generation of oxidative stress and TGF-β1 production play important roles in liver fibrogenesis. We have previously shown that HCV increases hepatocyte TGF-β1 expression. However, the mechanisms by which this induction occurs have not been well studied. We explored the possibility that HCV infection regulates TGF-β1 expression through generation of reactive oxygen species (ROS), which act through one or more of the p38 MAPK, ERK, JNK, and NFκB signaling pathways to induce TGF-β1 expression.

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Hepatocellular carcinoma (HCC) is a common human malignancy. Its high mortality rate is mainly a result of high intrahepatic recurrence and portal venous invasion (PVI). We previously reported that the development of PVI is related to levels of des-gamma-carboxy prothrombin (DCP), a serum protein that increases at a notably higher rate in patients with HCC. Because DCP is produced by a vitamin K shortage, we examined the biological effects of extrinsic supplementation of vitamin K 2 in HCC cells in vitro and in vivo. H epatocellular carcinoma (HCC) is one of the major malignancies in the world. 1 Recent progress in treatment modalities has improved the prognosis of patients with HCC. 2-4 However, the long-term prognosis remains disappointing because of the frequent recurrence of HCC 5 and the development of portal venous invasion (PVI) of HCC in 16%-65% of patients, 6,7 resulting in the extensive spread of tumor cells throughout the liver. 8 Prior to this study, we and others observed PVI more frequently in HCC patients with positive des-gammacarboxy prothrombin (DCP), a serum protein induced by the absence of vitamin K, than in patients with negative DCP. 9 Moreover, serum DCP levels at the time of the HCC diagnosis were found in a prospective study to be the most significant predisposing factor for the development of PVI. 9 Prothrombin is a vitamin K-dependent plasma coagulation factor that is synthesized in the liver. The precursor of prothrombin contains 10 glutamic acid residues in its amino-terminal domain. These residues must undergo complete carboxylation to ␥-carboxyglutamic acid in the presence of vitamin K for prothrombin to display coagulation activity. DCP is an abnormal prothrombin that is not completely carboxylated. Although the precise causes of DCP production are unknown, 10 the concentration of vitamin K is normal in nontumorous parts of the liver but is decreased significantly in HCC tissues. 11 Vitamin K is a fat-soluble essential vitamin; its only known physiological role is as a cofactor for ␥-glutamylcarboxylase, which acts on several blood-clotting pro-